U.S. Pat. No. 4,837,381 discloses a microsphere composition of fat or wax or mixture thereof and a biologically active protein, peptide or polypeptide suitable for parenteral administration. The patent discloses the utility of the compositions for slow release of a protein, peptide or polypeptide in a parenteral administration, and discloses methods for increasing and maintaining increased levels of growth hormone in the blood of treated animals for extended periods of time and thereby increasing weight gains in animals and increasing milk production of lactating animals by the administration of compositions of the invention.
There are special problems in the development of sustained release pharmaceutical compositions of biologically active macromolecules due to the size and complexity of the macromolecules, particularly proteins, which are susceptible to chemical and structural alteration upon mixing with pharmaceutical excipients, upon processing and upon storage. These problems are understood by those skilled in the art of pharmaceutical formulation and can be categorized as problems of chemical stability. Inadequate chemical stability of pharmaceutical compositions resulting from irreversible alteration of the structure of the macromolecules and/or interactions with the excipients can result in compositions that are either inactive or do not provide the expected level of biological response.
Another category of problems for pharmaceutical formulations is physical stability. One obvious example is attrition of tablets or implants during processing, packaging, or storage. Another example is a physical separation of a cream, paste or gel into component parts which can lead to a heterogeneous distribution of active ingredient as well as alteration of the consistency. The consequence of such physical deterioration of the formulation can be loss of the desired ease of use characteristics and an unpredictable dosing to the patient. Less obvious physical changes in a pharmaceutical formulation include various alterations to the crystalline or microscopic structure of the excipients. These types of changes can lead to marked alterations in the release of active agents. It should be clear that changes in the physical stability of pharmaceutical dosage forms whether they be for oral or parenteral administration would be most problematic for sustained release preparations. It is the sine qua non of commercially viable sustained release pharmaceutical dosage forms that they have maintained release characteristics across production lots and after relatively long periods of time in storage. Physical stability of the pharmaceutical dosage form is intended to describe both constancy of the handling characteristics such as hardness, flowability, or viscosity, and constancy of pharmacological performance.
It is an object of this invention to provide stable compositions for parenteral administration. It is another object of this invention to provide a novel method of preparing these stable compositions. It is still another object to provide a microsphere composition which can be packaged as a ready to use formulation with good storagability. These and other objects will become apparent in the description of the invention.